Abstract The conversion of soluble proteins into amyloid fibers is a feature of a number of clinical disorders including Alzheimer[unreadable]s, Huntington[unreadable]s and type II diabetes. In each case, the precursor protein has distinct primary, secondary and tertiary structure. However, the resultant fibers are remarkably similar at the histological and ultrastructural level. Fiber formation kinetics are similar to crystallization in that there exists a prolonged lag phase in which fiber is undetectable. This is followed by a cooperative transition to the fibrous state. Interestingly, it is the intermediate states sampled during the lag phase that have been identified as the most cytotoxic species. Central to all these disorders, therefore, is the need to identify the molecular basis of the underpinning conformational changes. The overall goal of this proposal is to determine the molecular basis for amyloid conversion in two medically relevant systems. First, islet amyloid polypeptide (IAPP), a 37 residue peptide hormone that is cosecreted with insulin by the [unreadable]-cells of the pancreas. In type II diabetics, IAPP deposits as amyloid and is correlated with [unreadable]-cell death. Second, renal diseases which necessitate treatment by dialysis result in the deposition of [unreadable]-2 microglobulin ([unreadable]2m) amyloid in the joints giving rise to a variety of skeletal pathologies. In both of these systems, it is wild-type, unmodified forms of the protein which aggregate. Our approach has been to identify changes in the in vivo environment of theses proteins and to determine the molecular impact of these changes on their folding and fibrillogenesis. Our first major aim is to determine the conformation and oligomeric changes associated with fibrillar assembly of IAPP. Importantly, we have determined that fibrillogenesis of IAPP can be catalyzed by lipid bilayers in a manner consistent with the consequences of metabolic change in diabetics and the obese. Furthermore, cytotoxicity of amyloid is strongly associated with perturbation in cellular membrane integrity. We will determine the molecular basis for these effects. In [unreadable]2m, our group recently discovered a novel interaction between [unreadable]2m and Cu(II) which can uniquely give rise to the nucleation of amyloid fibers under conditions consistent with those present during hemodialysis therapy. Our second major aim is to determine the structural and energetic basis for divalent induced amyloidosis. Our aims will be met by combined use of mutagenesis, optical, NMR and crystallographic techniques to elucidate the perturbation of protein structure that results in fibrillogenesis. There are many different proteins each performing a unique function in the body. These are complex machines composed of thousands of atoms which must fold up to the right structure in order to do their work. A group of diseases, including Alzheimer[unreadable]s, diabetes, and renal failure share a common feature in that a particular protein misfolds into fibrous structures that cause pathology. The aim of this work is to determine the rules governing such missteps using the proteins islet amyloid polypeptide, which misfolds in type II diabetes, and [unreadable]-2 microglobulin which misfolds in renal failure patients treated with hemodialysis.